# US 11,306,098 B2 · Substituted pyrrolo[1,2-a]pyrazines and pyrrolo[1,2-a][1,4]diazepines as TREX1 inhibitors

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- Number: US 11,306,098 B2
- Document ID: US11306098B2
- Status: Granted
- Kind: B2
- Application number: 16/829,655
- Filed: 2020-03-25
- Published: 2020-10-08
- Granted: 2022-04-19
- Earliest claimed: 2019-04-08
- Assignees: Venenum Biodesign, LLC
- Applicants: Venenum Biodesign, LLC
- Inventors: Jeffrey J. Letourneau; Kiruthika Selvarangan Elamparuthi; Chia-Yu Huang; Venugopalareddy Bommireddy Venkata
- Web page: https://patentgrep.com/patent/US11306098B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/5517: condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
- A61P 35/00: Antineoplastic agents
- C07D 243/08: not condensed with other rings
- C07D 471/04: Ortho-condensed systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides compounds of Formula I wherein X, R1, R2, R3 and R4 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are effective at modulating the TREX1 protein and thus can be used as medicaments for treating or preventing disorders affected by the inhibition of TREX1.

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C1-C6 alkylene-NR5C(O)—, —C1-C6 alkylene-NR5S(O)2—, —C(O)NR5—, —C(O)NR5S(O)2—, or a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains at least 1 nitrogen heteroatom;
R1 is C1-C6 alkylene-NR5R6 or NR5R6;
R2 is C1-C6 alkyl, C1-C6 alkylene-O—C6-C10 aryl, C1-C6 alkylene-O-5- to 10-membered heteroaryl, C1 -C6 alkylene-S—C6-C10 aryl, C1-C6 alkylene-S—5- to 10-membered heteroaryl, C1-C6 alkylene-S(O)—C6-C10 aryl, C1-C6 alkylene-S(O)-5- to 10-membered heteroaryl, C1-C6 alkylene-S(O)2—C6-C10 aryl, C1-C6 alkylene-S(O)2-5 to 10-membered heteroaryl, C1-C6 alkylene-C6-C10 aryl, or C1-C6 alkylene-5- to 10-membered heteroaryl, wherein any C6-C10 aryl or 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C4 haloalkyl;
R3 is C1-C6 alkyl, C1-C6 alkylene-C3-C6 cycloalkyl, C1-C6 alkylene-C6-C10 aryl, C1-C6 alkylene-5- to 10-membered heteroaryl, or C6-C10 aryl, wherein any C3-C6 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C6 haloalkyl;
R4 is C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR8R9, C(O)NR8S(O)2R9, C(O)NR8S(O)2NR28R29, C(O)OH, NR8R9, NR28C(O)NR8R9, NR28C(O)NR8S(O)2R9, NR8S(O)2R9, OH, ONR8R9, SR9, S(O)R9, S(O)2R9, S(O)2NR8R9, S(O)2OH, C6-C10 aryl, and a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C6-C10 aryl or 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, ═O, OC1-C4 alkyl, and OC1-C4 haloalkyl;
each R5 is independently H, C1-C6 alkyl, or C1-C6 haloalkyl;
each R6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R7;
each R7 is independently C1-C6 alkyl or OC1-C6 alkyl;
each R8 is independently H, C1-C4 alkyl, C1-C4 haloalkyl, C(O)C1-C4 alkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl;
each R9 is independently H, C1-C4 alkyl, OH, OC1-C4 alkyl, C3-C6 cycloalkyl, or C6-C10 aryl, wherein each C1-C4 alkyl, OC1-C4 alkyl, C3-C6 cycloalkyl, and C6-C10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, ═O, OC1-C4 alkyl, and OC1-C4 haloalkyl;
each R28 is independently H, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl; and
each R29 is independently H, C1-C4 alkyl, C1-C4 haloalkyl, OC1-C4 alkyl, or OC1-C4 haloalkyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C1-C6 alkylene-NR5C(O)—, —C(O)NR5—, —C(O)NR5S(O)2—, or a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains at least 1 nitrogen heteroatom;
R2 is C1-C6 alkyl, C1-C6 alkylene-O—C6-C10 aryl, C1-C6 alkylene-S—C6-C10 aryl, C1-C6 alkylene-S(O)—C6-C10 aryl, C1-C6 alkylene-S(O)2-C6-C10 aryl, or C1-C6 alkylene-C6-C10 aryl, wherein any C6-C10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C4 haloalkyl;
R3 is C1-C6 alkyl, C1-C6 alkylene-C6-C10 aryl, C1-C6 alkylene-5- to 10-membered heteroaryl, or C6-C10 aryl, wherein any C6-C10 aryl or the 5- to 10-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C6 haloalkyl;
R4 is C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR8R9, C(O)OH, OH, C6-C10 aryl, and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C6-C10 aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, ═O, OC1-C4 alkyl, and OC1-C4 haloalkyl;
each R8 is independently H, C1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 alkyl; and
each R9 is independently H, C1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C1-C6 alkylene-NR5C(O)—, —C(O)NR5—, or a 5-membered heteroarylene, wherein the 5-membered heteroarylene contains at least 1 nitrogen heteroatom;
R2 is C1-C6 alkyl, C1-C6 alkylene-O—C6-C10 aryl, C1-C6 alkylene-S—C6-C10 aryl, or C1-C6 alkylene-C6-C10 aryl, wherein any C6-C10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C alkyl, C1-C4haloalkyl, OH, OC1-C4 alkyl, and OC1-C4 haloalkyl;
R3 is C1-C6 alkyl, C1-C6 alkylene-C6-C10 aryl, C1-C6 alkylene-5-membered heteroaryl, or C6-C10 aryl, wherein any C6-C10 aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C6 haloalkyl;
R4 is C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR8R9, C(O)OH, OH, C6-C10 aryl, and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C6-C10 aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, ═O, OC1-C4 alkyl, and OC1-C4 haloalkyl;
each R8 is independently H, C1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 alkyl; and
each R9 is independently H, C1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 alkyl.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C(O)NR5—;
R1 is NR5R6;
R2 is C1-C6 alkylene-C6-C10 aryl, wherein the C6-C10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, OH, and OC1-C4 haloalkyl;
R3 is C1-C6 alkylene-C6-C10 aryl, wherein the C6-C10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, and OH;
R4 is C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of C(O)OH, OH, C6-C10 aryl, and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein any C6-C10 aryl or 5-membered heteroaryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, ═O, OC1-C4 alkyl, and OC1-C4 haloalkyl;
each R5 is independently H or CH3; and
R6 is H or C1-C6 alkyl.

### Claim 5 (depends on 4)

The compound of claim 4, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:

### Claim 6 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R4 is C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with 1 substituent selected from the group consisting of C(O)OH and 5-membered heteroaryl, wherein the 5-membered heteroaryl contains at least 1 nitrogen heteroatom, and further wherein the 5-membered heteroaryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, ═O, OC1-C4 alkyl, and OC1-C4 haloalkyl.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C1-C6 alkylene-NR5C(O)— or —C(O)NR5—;
R2 is C1-C6 alkyl, C1-C6 alkylene-O—C6-C10 aryl, or C1-C6 alkylene-C6-C10 aryl, wherein any C6-C10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C4 haloalkyl;
R3 is C1-C6 alkyl, C1-C6 alkylene-C6-C10 aryl, or C6-C10 aryl, wherein any C6-C10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C6 haloalkyl;
R4 is C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR8R9, C(O)OH, OH, and C6-C10 aryl, wherein any C6-C10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C4 haloalkyl;
each R8 is independently H, C1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 alkyl; and
each R9 is independently H, C1-C4 alkyl, C1-C4 haloalkyl, or OC1-C4 alkyl.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C1-C6 alkylene-NR5C(O)— or —C(O)NR5—;
R2 is C1-C6 alkyl or C1-C6 alkylene-C6-C10 aryl, wherein the C6-C10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C4 haloalkyl;
R3 is C1-C6 alkyl, C1-C6 alkylene-C6-C10 aryl, or C6-C10 aryl, wherein any C6-C10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C6 haloalkyl;
R4 is C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of CN, C(O)NR8R9, C(O)OH, OH, and C6-C10 aryl, wherein any C6-C10 aryl is optionally and independently substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, OH, OC1-C4 alkyl, and OC1-C4 haloalkyl;
each R8 is independently H, C1-C4 alkyl, or C1-C4 haloalkyl; and
each R9 is independently H, C1-C4 alkyl, or C1-C4 haloalkyl.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
X is —C(O)NR5—;
R1 is NR5R6;
R2 is C1-C6 alkyl or C1-C6 alkylene-C6-C10 aryl, wherein the C6-C10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, and OH;
R3 is C1-C6 alkyl, C1-C6 alkylene-C6-C10 aryl, or C6-C10 aryl, wherein the C6-C10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, and OH;
R4 is C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1 or more substituents independently selected from the group consisting of C(O)OH, OH, and C6-C10 aryl, wherein any C6-C10 aryl is optionally substituted with 1 or more substituents independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 haloalkyl, and OH;
each R5 is independently H or C1-C6 alkyl;
R6 is H, C1-C6 alkyl, or C(O)R7; and
R7 is C1-C6 alkyl or OC1-C6 alkyl.

### Claim 10 (depends on 6)

The compound of claim 6, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound, or pharmaceutically acceptable salt or stereoisomer thereof, is selected from the group consisting of:
or a solvate or tautomer thereof.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, alone or in combination with another therapeutic agent.

### Claim 13 (depends on 12)

The pharmaceutical composition of claim 12, wherein the other therapeutic agent is selected from the group consisting of an anti-cancer agent, an anti-viral compound, an adjuvant, an antigen, a biotherapeutic agent, a cell transfected with a gene that encodes an immune stimulating cytokine, a checkpoint inhibitor, a chemotherapeutic agent, a cytotoxic agent, an immunogenic agent, an immunomodulatory cell line, a lipid, a liposome, and a peptide.